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Multiple templates-based homology modeling enhances structure quality of AT1 receptor: validation by molecular dynamics and antagonist docking

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Abstract

We present a comparative account on 3D-structures of human type-1 receptor (AT1) for angiotensin II (AngII), modeled using three different methodologies. AngII activates a wide spectrum of signaling responses via the AT1 receptor that mediates physiological control of blood pressure and diverse pathological actions in cardiovascular, renal, and other cell types. Availability of 3D-model of AT1 receptor would significantly enhance the development of new drugs for cardiovascular diseases. However, templates of AT1 receptor with low sequence similarity increase the complexity in straightforward homology modeling, and hence there is a need to evaluate different modeling methodologies in order to use the models for sensitive applications such as rational drug design. Three models were generated for AT1 receptor by, (1) homology modeling with bovine rhodopsin as template, (2) homology modeling with multiple templates and (3) threading using I-TASSER web server. Molecular dynamics (MD) simulation (15 ns) of models in explicit membrane-water system, Ramachandran plot analysis and molecular docking with antagonists led to the conclusion that multiple template-based homology modeling outweighs other methodologies for AT1 modeling.

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Acknowledgments

We thank University Grants Commission (UGC), New Delhi, for the award of Senior Research Fellowship to S. Pandian. Thanks are due to UGC-NRCBS, MKU, for providing the Lab facilities.

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Authors and Affiliations

  1. School of Chemistry, Madurai Kamaraj University, Madurai, 625 021, Tamil Nadu, India

    Pandian Sokkar & Murugesan Ramachandran

  2. School of Biological Sciences, Madurai Kamaraj University, Madurai, 625 021, Tamil Nadu, India

    Shylajanaciyar Mohandass & Murugesan Ramachandran

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  1. Pandian Sokkar
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  2. Shylajanaciyar Mohandass
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  3. Murugesan Ramachandran
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Correspondence to Murugesan Ramachandran.

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Sokkar, P., Mohandass, S. & Ramachandran, M. Multiple templates-based homology modeling enhances structure quality of AT1 receptor: validation by molecular dynamics and antagonist docking. J Mol Model 17, 1565–1577 (2011). https://doi.org/10.1007/s00894-010-0860-z

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  • DOI: https://doi.org/10.1007/s00894-010-0860-z

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